Abstract Alzheimer disease (AD) is characterized by progressive synaptic dysfunction, neurodegeneration, neuroinflammation and CNS accumulation of amyloid plaques and hyperphosphorylated tau. In 2016, America had an estimated 5.4 million AD cases, including people living with HIV (PLWH). With successful combined antiretroviral therapy (cART), PLWH live longer but remain more at risk for chronic conditions such as cancer, cardiovascular disease, and neurodegenerative dementia, including AD. Over two-thirds of the 37.9 million people living with HIV (PLWH) infection are in Africa where the high burden of infections with bacteria, fungi, parasites, and viruses that contribute to inflammation, other than HIV-1, is exacerbated by HIV-1 disease and may persist despite HIV-1 viral load suppression. Our preliminary findings suggest that amyloid deposition and tau neuropathology are elevated in the brain tissue of HIV infected individuals, and are detectable at a much younger age than in uninfected subjects in Zambia, a sub-Saharan African country in the heart of the HIV/AIDS epidemic. Our data indicates that HIV-infection may indirectly potentiate development and progression of AD- like pathologies, despite effective mitigation of HIV replication. Our overall goal is to identify additional factors, such as microbial infections and dysregulated cellular gene expression that may co-associate with amyloid and tau neuropathology in HIV-1 infected individuals. The current study derives from a parent post-mortem investigation of the impact of cannabis on inflammation and HIV-1 reservoirs in Zambia. Our preliminary observational findings of accelerated CNS amyloid and tau deposition in HIV infection derive from a previous Alzheimer?s-focused supplement. We are leveraging the existing infrastructure and expertise and the lesson learned from an earlier supplemental project to refine our collection and analyses of post-mortem CNS samples. We will test our hypothesize that differentials in AD-like neuropathological manifestations will associate with CNS co-infections and tissue transcriptome alterations that distinguish HIV-1 infected from HIV-1 negative subjects. This will be carried out by: 1) Conducting systematic histopathologic analyses of brain tissues to determine the extent to which amyloid and tau neuropathology, neurodegeneration and neuroinflammation are differential between HIV-1 infected and uninfected African individuals; 2) Characterizing and comparing CNS tissue transcriptomes in brain tissues with and without amyloid and tau neuropathology, and HIV infection. The results will provide insights into interactions between infections and host gene expression that may drive premature development of amyloidopathy and tauopathy in the HIV infected. In turn, the findings may reveal potential biomarkers of early neuropathology in the HIV-infected and help guide treatment approaches.